Dissection of mature human T cells into those that mediate predominantly helper/inducer effects (Leu 3, T4) and those that mediate predominantly suppressor/cytotoxic effects (Leu 2, T8) was made possible with monoclonal antibodies. Using the mixed leukocyte reaction (MLR) as a model system, we have further fractionated these two major T lineages into subsets with relatively narrow functional repetoires. For example, immunoglobulin synthesis induced in MLR was shown to be regulated by sequential interactions between subsets of Leu suppressor inducer cells, Leu\2+,3-DR+suppressor-amplifier cells, and Leu 2+,3-,DR- suppressor-effector cells. We further showed that Leu 3+cells capable of helping B cell differentiation and Ig synthesis can be distinguished from Leu 3+cells that do not provide help on the basis of their expression of the Leu 8 marker. Finally, precursors of Leu 2 suppressor-effector cells (Ts) were distinguished from precursors of Leu 2+cytotoxic cells on the basis of their differential expression of the 9.3 antigen. In summary, these data indicate that human T lymphocytes consist of a larger number of functionally distinct subsets than heretofore recognized, distinguishable from one another with combinations of monoclonal antibodies directed at cell surface markers. (LB)